DESCRIPTION: As genetic effects on human health have been extensively studied, epigenetic effects, which represent factors such as the environment or dynamic cellular regulation, are still poorly understood, although they are believed to play an equally important role in human health. DNA methylation is repressive epigenetic marker that associates with normal development, aging process, and diseases such as cancer, mental disorders, and respiratory disorders. Mapping and understanding whole-genome DNA methylation (methylome) under the context of personal genomics adds an essential dimension of insights to personalized medicine. Rapid advances in DNA sequencing technologies have led to a detailed understanding of the human genome and epigenome. Yet, in spite of these advances, most genomics studies to date are based on a single reference of human genome and have given little consideration to a crucial aspect of human genetics: humans are diploid and differences between paternal and maternal chromosomes can affect many key biological mechanisms that are related to human health. In particular allele-specific DNA methylation is a key mechanism of allele-specific gene silencing, a phenomenon termed genomic imprinting. Allele-specific DNA methylation is shown to be important for normal embryonic development. However, its dynamics in human cells and its association with human health are poorly understood. The goal of this project is to develop a new technology to completely phase human methylome and to study the dynamics of human methylome at chromosome level. The first two years of the project (K99 phase) will be carried out at Dr. Michael Snyder's lab. During the K99 phase, Dr. Dan Xie will develop and test the phasing technology and apply this technology to phase the methylome of multiple cell types from one individual. This will reveal the dynamics of allele-specific DNA methylation in human cells and provide insights about the regulatory functions of DNA methylation. Having optimized the phasing technology and with the experience and results from the K99 study, as an independent researcher, Dr. Dan Xie will continue to phase the methylome in multiple lymphoblastoid cell lines from different individuals to understand the variation of allele- specifi DNA methylation between individuals (R00 phase). The integration of existing large-scale genomics data, such as ENCODE and GWAS data, and the phased methylome data generated in this study will deepen our understanding of epigenetic regulation in much more detail.